We propose to create an Interdisciplinary Research Consortium (IRC) that will transform the process of drug discovery by integrating novel approaches from genomics, chemistry, imaging and computational science. Our approach is to augment the now traditional approach of target-based screening so that drugs can be developed for situations where evidence points not to a single protein, but rather to a biological process involving many proteins, or an alteration in the state of the cell. With this goal, we propose the pursue the following hypotheses: 1) that live cell screens based on gene-expression signatures (GE-HTS) and quantitative high-throughput live cell imaging (LCI-HTS) can be developed as a primary route to discovering new drugs, and 2) that when combined with novel approaches from Component B (Discovery Pipeline) and Component C (Target ID), these projects will support the discovery of potent and safe drugs with novel mechanisms of action. In order to test these hypotheses and drive the development of new approaches to drug development, Component D will apply the capabilities developed in Component B (Discovery Pipeline) and Component C (Target ID) to six demonstration projects in three areas: 1) well-credentialed genes and pathways that are highly relevant to human disease, and yet to date have failed to yield successful drugs; 2) based on knowledge of effective drugs in the clinic, and 3) pathways newly identified in vivo by human genetics as playing causal roles in poorly treated diseases. Each of the six demonstration projects will proceed through four stages: 1) development of cell-based assays, 2) screening for small-molecule leads, 3) identification of the target and medicinal chemistry to optimize the lead compounds, and 4) evaluating efficacy and toxicity using in vivo animal models of disease. In summary, driven by our evaluation of the limitations and opportunities offered by traditional and novel approaches to drug development, and combining the interdisciplinary approaches described in Component B (Discovery Pipeline) and Component C (Target ID) with disease-specific expertise in each of these six demonstration projects, Component D aims to validate a new paradigm for drug discovery, and make significant headway in discovering new small molecules for the treatment of important human diseases.